Abstract There is growing evidence that moderate exposure to alcohol during development can lead to behavioral and cognitive deficits that can persist throughout the lifespan. Cognitive impairments associated with Fetal Alcohol Spectrum Disorders (FASD) include abnormalities in learning and memory, executive control and social behaviors and are often characterized by a hyper-focus on one particular task or aspect of a task, to the detriment of other important behaviors. We have recently shown that moderate prenatal alcohol exposure (PAE) can impair executive control in adulthood and that behavioral impairments are accompanied by significant alterations in coherence in the orbitofrontal cortex during choice. Both behavioral deficits and cortical alterations are found when GluN2B subunit containing N-Methyl-D-Aspartate receptors (NMDAR) are lost in the OFC. Given preliminary data that GluN2B is significantly reduced in the OFC after PAE, we propose to investigate whether impairments in behavioral flexibility are driven by alterations in cortical coherence mediated by alterations in NMDAR expression and function and whether these deficits can be rescued. We propose to integrate a well-established voluntary drinking paradigms for moderate PAE with touch-screen behavioral assays, in vivo and ex vivo electrophysiology and optogenetic stimulation. First, we will express channel rhodopsin (ChR2) in the cortex of PAE and SAC mice and examine whether direct stimulation will rescue behavioral flexibility impairments in PAE mice. Next, given evidence that GluN2B is downregulated after PAE and that his subunit contributes to establishing cortical coherence, we will investigate whether behavioral deficits in the model are mediated by alterations in GluN2B subunit expression and recruitment required to induce plasticity and support behavioral flexibility. Finally, we will examine whether changes in connectivity between OFC and dS drives asynchrony and perseveration. We will use retrograde expression to fluorescently tag OFC-dS neurons and characterize function of NMDAR via ex vivo slice physiology. Then we will utilize retrograde expression of ChR2 to test if stimulation restricted to OFC-dS neurons is sufficient to rescue the behavioral deficits. Taken together the completion of these aims will elucidate the mechanisms of cognitive impairment in FASD and provide an important tool for developing more effective therapies for executive dysfunction.